2-(4-bromo or 4-iodo phenylamino) benzoic acid derivatives

ABSTRACT

Phenylamino benzoic acid, benzamides, and benzyl alcohol derivatives of the formula  
                 
 
     where R 1 , R 2 , R 3 , R 4 , R 5 , and R 6  are hydrogen or substituent groups such as alkyl, and where R 7  is hydrogen or an organic radical, and Z is COOR 7 ,  
     tetrazolyl, CONR 6 R 7 , or CH 2 OR 7 , are potent inhibitors of MEK and, as such, are effective in treating cancer and other proliferative diseases such as inflammation, psoriasis and restenosis, as well as stroke, heart failure, and immunodeficiency disorders.

FIELD OF THE INVENTION

[0001] This invention provides benzoic acid and amide derivatives ofanthranilic acids which inhibit certain dual specificity kinase enzymesinvolved in proliferative diseases such as cancer and restenosis.

BACKGROUND OF THE INVENTION

[0002] Proliferative diseases are caused by a defect in theintracellular signaling system, or the signal transduction mechanism ofcertain proteins. Cancer, for example, is commonly caused by a series ofdefects in these signaling proteins, resulting from a change either intheir intrinsic activity or in their cellular concentrations. The cellmay produce a growth factor that binds to its own receptors, resultingin an autocrine loop, which continually stimulates proliferation.Mutations or overexpression of intracellular signaling proteins can leadto spurious mitogenic signals within the cell. Some of the most commonmutations occur in genes encoding the protein known as Ras, which is aG-protein that is activated when bound to GTP, and inactivated whenbound to GDP.

[0003] The above mentioned growth factor receptors, and many othermitogenic receptors, when activated, lead to Ras being converted fromthe GDP-bound state to the GTP-bound state. This signal is an absoluteprerequisite for proliferation in most cell types. Defects in thissignaling system, especially in the deactivation of the Ras.GTP complex,are common in cancers, and lead to the signaling cascade below Ras beingchronically activated.

[0004] Activated Ras leads in turn to the activation of a cascade ofserine/threonine kinases. One of the groups of kinases known to requirean active Ras.GTP for its own activation is the Raf family. These inturn activate MEK, (eg, MEK₁ and MEK₂) which then activates MAP kinase.Activation of MAP kinase by mitogens appears to be essential forproliferation, and constitutive activation of this kinase is sufficientto induce cellular transformation. Blockade of downstream Ras signaling,for example by use of a dominant negative Raf-1 protein, can completelyinhibit mitogenesis, whether induced from cell surface receptors or fromoncogenic Ras mutants. Although Ras is not itself a protein kinase, itparticipates in the activation of Raf and other kinases, most likelythrough a phosphorylation mechanism. Once activated, Raf and otherkinases phosphorylate MEK on two closely adjacent serine residues, S²¹⁸and S²²² in the case of MEK-1, which are the prerequisite for activationof MEK as a kinase. MEK in turn phosphorylates MAP kinase on both atyrosine, y¹⁸⁵, and a threonine residue, T¹⁸³, separated by a singleamino acid. This double phosphorylation activates MAP kinase at least100-fold, and it can now catalyze the phosphorylation of a large numberof proteins, including several transcription factors and other kinases.Many of these MAP kinase phosphorylations are mitogenically activatingfor the target protein, whether it be another kinase, a transcriptionfactor, or other cellular protein. MEK is also activated by severalkinases other than Raf-1, including MEKK, and itself appears to be asignal integrating kinase. As far as is currently known, MEK is highlyspecific for the phosphorylation of MAP kinase. In fact, no substratefor MEK other than MAP kinase has been demonstrated to date, and MEKdoes not phosphorylate peptides based on the MAP kinase phosphorylationsequence, or even phosphorylate denatured MAP kinase. MEK also appearsto associate strongly with MAP kinase prior to phosphorylating it,suggesting that phosphorylation of MAP kinase by MEK may require a priorstrong interaction between the two proteins. Both this requirement andthe unusual specificity of MEK are suggestive that it may have enoughdifference in its mechanism of action to other protein kinases thatselective inhibitors of MEK, possibly operating through allostericmechanisms rather than through the usual blockade of the ATP bindingsite, may be found.

[0005] This invention provides compounds which are highly specificinhibitors of the kinase activity of MEK. Both in enzyme assays andwhole cells, the compounds inhibit the phosphorylation of MAP kinase byMEK, thus preventing the activation of MAP kinase in cells in which theRas cascade has been activated. The results of this enzyme inhibitioninclude a reversal of transformed phenotype of some cell types, asmeasured both by the ability of the transformed cells to grow in ananchorage-independent manner and by the ability of some transformed celllines to proliferate independently of external mitogens.

[0006] The compounds provided by this invention are 2-(phenylamino)benzoic acid, tetrazole, ester, amide, and benzyl alcohol derivatives,in which the phenyl ring is substituted at the 4-position with bromo oriodo. U.S. Pat. No. 5,155,110 discloses a wide variety of fenamic acidderivatives, including certain 2-(phenylamino) benzoic acid derivatives,as anti-inflammatory agents. The reference fails to describe thecompounds of this invention or their kinase inhibitory activity.

SUMMARY OF THE INVENTION

[0007] This invention provides 4-bromo and 4-iodo phenylamino benzoicacid derivatives which are selective MEK kinase inhibitors and as suchare useful for treating proliferative diseases such as cancer,psoriasis, and restenosis. The compounds are defined by Formula I

[0008] wherein:

[0009] R₁ is hydrogen, hydroxy, C₁-C₈ alkyl, C₁-C₈ alkoxy, halo,trifluoromethyl, or CN;

[0010] R₂ is hydrogen;

[0011] R₃, R₄, and R₅ independently are hydrogen, hydroxy, halo,trifluoromethyl, C₁-C₈ alkyl, C₁-C₈ alkoxy, nitro, CN, or —(O orNH)_(m)—(CH₂)_(n)—R₉, where R₉ is hydrogen, hydroxy, CO₂H, or NR₁₀ R₁₁;

[0012] n is 0-4;

[0013] m is 0 or 1;

[0014] R₁₀ and R₁₁ independently are hydrogen or C₁-C₈ alkyl, or takentogether with the nitrogen to which they are attached, can complete a3-10 member cyclic ring optionally containing one, two, or threeadditional heteroatoms selected from 0, S, NH, or N—C₁-C₈ alkyl;

[0015] Z is COOR₇, tetrazolyl, CONR₆R₇, CONHNR₁₀R₁₁, or CH₂OR₇;

[0016] R₆ and R₇ independently are hydrogen, C₁-C₈ alkyl, C₂-C₈ alkenyl,C₂-C₈ alkynyl,

[0017] aryl, heteroaryl, C₃-C₁₀ cycloalkyl, or C₃-C₁₀ (cycloalkyloptionally containing one, two, or three heteroatoms selected from O, S,NH, or N alkyl); or R₆ and R₇ together with the nitrogen to which theyare attached complete a 3-10 member cyclic ring optionally containing 1,2, or 3 additional heteroatoms selected from O, S, NH, or N alkyl;

[0018] and wherein any of the foregoing alkyl, alkenyl, and alkynylgroups can be unsubstituted or substituted by halo, hydroxy, alkoxy,amino, alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl,or heteroaryloxy, and the pharmaceutically acceptable salts thereof.Preferred compounds have Formula II

[0019] where R₁, R₃, R₄, R₅, R₆, and R₇ are as defined above. Especiallypreferred are compounds wherein R₁ is methyl or halo, and R₃, R₄, and R₅are halo such as fluoro or bromo.

[0020] The compounds of Formula II are carboxylic acids when R₇ ishydrogen, and are esters when R₇ is other than hydrogen. Compounds whichare analogous to the acids in physical and biological properties aretetrazolyl derivatives of Formula IIa

[0021] Another preferred group of compounds are amides Formula III

[0022] The most preferred compounds are those wherein R₁ is methyl, R₃is hydrogen or halo such as fluoro, R₄ is halo such as fluoro, and R₅ ishydrogen or halo such as fluoro, bromo, or chloro. Representativecompounds have the formulas

[0023] This invention also provides pharmaceutical formulationscomprising a compound of Formula I together with a pharmaceuticallyacceptable excipient, diluent, or carrier. Preferred formulationsinclude any of the foregoing preferred compounds together with anexcipient, diluent, or carrier.

[0024] The compounds of Formula I are potent and selective inhibitors ofMEK₁ and MEK₂ kinase enzymes. They are, therefore, useful to treatsubjects suffering from cancer, stroke, diabetes, Alzheimer's disease,cystic fibrosis, viral disease, heart failure, and proliferativediseases such as psoriasis, restenosis, autoimmune disease, andatherosclerosis. The compounds are especially well suited to treatcancers such as breast cancer, colon cancer, prostate cancer, skincancer, and pancreatic cancer. They are particularly well-suited for usein conjunction with conventional radiation therapy. The compounds arealso immunomodulatory agents and can be used to treat degenerativediseases where change in MEK activation leads to pathologies such ashepatomegaly and cardiomegaly. The invention provides a method ofinhibiting MEK enzymes and the foregoing diseases by administering to asubject an effective amount of a compound of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

[0025] As used herein, the term “aryl” means a cyclic, bicyclic, ortricyclic aromatic ring moiety having from five to twelve carbon atoms.Examples of typical aryl groups include phenyl, naphthyl, and fluorenyl.The aryl may be substituted by one, two, or three groups selected fromfluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino,alkylamino, or dialkylamino. Typical substituted aryl groups include3-fluorophenyl, 3,5-dimethoxyphenyl, 4-nitronaphthyl,2-methyl-4-chloro-7-aminofluorenyl, and the like.

[0026] The term “aryloxy” means an aryl group bonded through an oxygenatom, for example phenoxy, 3-bromophenoxy, naphthyloxy, and4-methyl-1-fluorenyloxy.

[0027] “Heteroaryl” means a cyclic, bicyclic, or tricyclic aromatic ringmoiety having from four to eleven carbon atoms and one, two, or threeheteroatoms selected from O, S, or N. Examples include furyl, thienyl,pyrrolyl, pyrazolyl, imidazolyl, triazolyl, thiazolyl, oxazolyl,xanthenyl, pyronyl, indolyl, pyrimidyl, naphthyridyl, pyridyl,benzinnidazolyl, and triazinyl. The heteroaryl groups can beunsubstituted or substituted by one, two, or three groups selected fromfluoro, chloro, bromo, iodo, alkyl, hydroxy, alkoxy, nitro, amino,alkylamino, or dialkylamino. Examples of substituted heteroaryl groupsinclude chloropyranyl, methylthienyl, fluoropyridyl,amino-1,4-benzisoxazinyl, nitroisoquinolinyl, and hydroxyindolyl.

[0028] The heteroaryl groups can be bonded through oxygen to makeheteroaryloxy groups, for example thienyloxy, isothiazolyloxy,benzofuranyloxy, pyridyloxy, and 4-methylisoquinolinyloxy.

[0029] The term “C₁-C₈ alkyl” means straight and branched chainaliphatic groups having from one to eight carbon atoms, preferably oneto four. Typical C₁-C₈ alkyl groups include methyl, ethyl, isopropyl,tert.-butyl, 2,3-dimethylhexyl, and 1,1-dimethylpentyl. The alkyl groupscan be unsubstituted or substituted by halo, hydroxy, alkoxy, amino,alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, orheteroaryloxy, as those terms are defined herein. Typical substitutedalkyl groups include chloromethyl, 3-hydroxypropyl,2-dimethylaminobutyl, and 2-(hydroxymethylamino)ethyl. Examples of aryland aryloxy substituted alkyl groups include phenylmethyl,2-phenylethyl, 3-chlorophenylmethyl,1,1-dimethyl-3-(2-nitrophenoxy)butyl, and 3,4,5-trifluoronaphthylmethyl.Examples of alkyl groups substituted by a heteroaryl or heteroaryloxygroup include thienylmethyl, 2-furylethyl, 6-furyloxyoctyl,4-methylquinolyloxymethyl, and 6-isothiazolylhexyl. Cycloalkylsubstituted alkyl groups include cyclopropylmethyl, 2-cyclohexyethyl,piperidyl-2-methyl, 2-(piperidin-1-yl)-ethyl, 3-(morpholin-4-yl)propyl.

[0030] “C₂-C₈ Alkenyl” means a straight or branched carbon chain havingone or more double bonds. Examples include but-2-enyl,2-methyl-prop-2-enyl, 1,1-dimethyl-hex-4-enyl,3-ethyl-4-methyl-pent-2-enyl, and 3-isopropyl-pent-4-enyl. The alkenylgroups can be substituted with halo, hydroxy, alkoxy, amino, alkylamino,dialkylamino, aryl, aryloxy, heteroaryl, or heteroyloxy, for example2-bromoethenyl, 3-hydroxy-2-butenyl, 1-aminoethenyl,3-phenylprop-2-enyl, 6-thienyl-hex-2-enyl, 2-furyloxy-but-2-enyl, and4-naphthyloxy-hex-2-enyl.

[0031] “C₂-C₈ Alkynyl” means a straight or branched carbon chain havingfrom two to eight carbon atoms and at least one triple bond. Typicalalkynyl groups include prop-2-ynyl, 2-methyl-hex-5-ynyl,3,4-dimethyl-hex-5-ynyl, and 2-ethyl-but-3-ynyl. The alkynyl groups canbe substituted as the alkyl and alkenyl groups, for example, by aryl,aryloxy, heteroaryl, or heteroaryloxy, for example4-(2-fluorophenyl)-but-3-ynyl, 3-methyl-5-thienylpent-4-ynyl,3-phenoxy-hex-4-ynyl, and 2-furyloxy-3-methyl-hex-4-ynyl.

[0032] The alkenyl and alkynyl groups can have one or more double bondsor triple bonds, respectively, or a combination of double and triplebonds. For example, typical groups having both double and triple bondsinclude hex-2-en-4-ynyl, 3-methyl-5-phenylpent-2-en-4-ynyl, and3-thienyloxy-hex-3-en-5-ynyl.

[0033] The term “C₃-C₁₀ cycloalkyl” means a nonaromatic ring or fusedrings containing from three to ten carbon atoms. Examples includecyclopropyl, cyclobutyl, cyclopenyl, cyclooctyl, bicycloheptyl,adamantyl, and cyclohexyl. The ring can optionally contain one, two, orthree heteroatoms selected from O, S, or NR₉. Such groups includetetrahydrofuryl, tetrahydropyrrolyl, octahydrobenzofuranyl, morpholinyl,piperazinyl, pyrrolidinyl, piperidinyl, octahydroindolyl, andoctahydrobenzothiofuranyl. The cycloalkyl groups can be substituted withthe same substituents as an alkyl and alkenyl groups, for example, halo,hydroxy, aryl, and heteroaryloxy. Examples include 3-hydroxycyclohexyl,2-aminocyclopropyl, 2-phenylpyrrolidinyl, and 3-thienylmorpholine-1-yl.

[0034] R₆ and R₇ can be taken together with the nitrogen to which theyare attached to complete a cyclic ring having from 3 to 10 members,which may contain 1, 2, or 3 additional heteroatoms selected from O, S,NH, or N alkyl. Examples of such cyclic rings include piperazinyl,piperidyl, pyrrolidinyl, morpholino, N-methylpiperazinyl, aziridynyl,and the like. Such rings can be substituted with halo, hydroxy, alkyl,alkoxy, amino, alkyl, and dialkylamino, aryl, aryloxy, heteroaryl, andheteroaryloxy. Typical examples include 3-hydroxy-pyrrolidinyl,2-fluoro-piperindyl, 4-(2-hydroxyethyl)-piperidinyl, and3-thienylmorpholino.

[0035] The 2-(4-bromo and 4-iodo phenylamino)-benzoic acid derivativesof Formula I can be prepared from commercially available startingmaterials utilizing synthetic methodologies well-known to those skilledin organic chemistry. A typical synthesis is carried out by reacting a4-bromo or 4-iodo aniline with a benzoic acid having a leaving group atthe 2-position to give a 2-(phenylamino)-benzoic acid. This process isdepicted in Scheme 1.

[0036] where L is a leaving group, for example halo such as fluoro.

[0037] The reaction of aniline and the benzoic acid derivative generallyis accomplished by mixing the benzoic acid with an equimolar quantity orexcess of the aniline in an unreactive organic solvent such astetrahydrofuran or toluene, in the presence of a base such as lithiumdiisopropylamide, n-butyl lithium, sodium hydride, triethylamine, andHunig's base. The reaction generally is carried out at a temperature ofabout −78° C. to about 100° C., and normally is complete within about 2hours to about 4 days. The product can be isolated by removing thesolvent, for example by evaporation under reduced pressure, and furtherpurified, if desired, by standard methods such as chromatography,crystallization, or distillation.

[0038] The 2-(phenylamino)-benzoic acid (eg, Formula I, where R₇ ishydrogen) can be reacted with an organic or inorganic base such aspyridine, triethylamine, calcium carbonate, or sodium hydroxide toproduce a pharmaceutically acceptable salt. The free acids can also bereacted with an alcohol of the formula HOR₇ (where R₇ is other thanhydrogen, for example methyl) to produce the corresponding ester.Reaction of the benzoic acid with an alcohol can be carried out in thepresence of a coupling agent. Typical coupling reagents include2-ethoxy-1-ethoxycarbonyl-1 ,2-dihydroquinoline (EEDQ),1,3-dicyclohexylcarbodiimide (DCC), bromo-tris(pyrrolidino)-phosphoniumhexafluorophosphate (PyBrOP), and (benzotriazolyloxy) tripyrrolidinophosphonium hexafluorophosphate (PyBOP). The phenylamino benzoic acidand alcohol derivative normally are mixed in approximately equimolarquantities in an unreactive organic solvent such as dichloromethane,tetrahydrofuran, chloroform, or xylene, and an equimolar quantity of thecoupling reagent is added. A base such as triethylamine ordiisopropylethylamine can be added to act as an acid scavenger ifdesired. The coupling reaction generally is complete after about 10minutes to 2 hours, and the product is readily isolated by removing thereaction solvent, for instance by evaporation under reduced pressure,and purifying the product by standard methods such as chromatography orcrystallizations from solvents such as acetone, diethyl ether, orethanol.

[0039] The benzamides of the invention, Formula I where Z is CONR₆R₇,are readily prepared by reacting the foregoing benzoic acids with anamine of the formula HNR₆R₇. The reaction is carried out by reactingapproximately equimolar quantities of the benzoic acid and amine in anunreactive organic solvent in the presence of a coupling reagent.Typical solvents are chloroform, dichloromethane, tetrahydrofuran,benzene, toluene, and xylene. Typical coupling reagents include DCC,EEDQ, PyBrOP, and PyBOP. The reaction is generally complete after about10 minutes to about 2 hours when carried out at a temperature of about0° C. to about 60° C. The product amide is readily isolated by removingthe reaction solvent, for instance by evaporation, and furtherpurification can be accomplished by normal methods such aschromatography, crystallization, or distillation. The hydrazides(z=CONHNR₁₀R₁₁) are similarly prepared by coupling a benzoic acid with ahydrazine of the formula H₂HNR₁₀R₁.

[0040] The benzyl alcohols of the invention, compounds of Formula Iwhere Z is CH₂OR₆ and R₆ is hydrogen, are readily prepared by reductionof the corresponding benzoic acid according to the following scheme

[0041] Typical reducing agents commonly employed include borane intetrahydrofuran. The reduction normally is carried out in an unreactiveorganic solvent such as tetrahydrofuran, and generally is completewithin about 2 hours to about 24 hours when conducted at a temperatureof about 0° C. to about 40° C.

[0042] The following detailed examples illustrate specific compoundsprovided by this invention.

EXAMPLE 1

[0043] 4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid

[0044] To a stirring solution comprised of 3.16 g (0.0133 mol) of2-amino-5-iodotoluene in 5 mL of tetrahydrofuran at −78° C. was added 10mL (0.020 mol) of a 2.0 M lithium diisopropylamide intetrahydrofuran/heptane/ethenylbenzene (Aldrich) solution. The resultinggreen suspension was stirred vigorously for 15 minutes, after which timea solution of 1.00 g (0.00632 mol) of 2,4-difluorobenzoic acid in 10 mLof tetrahydrofuran was added. The reaction temperature was allowed toincrease slowly to room temperature, at which temperature it was stirredfor 2 days. The reaction mixture was concentrated. Aqueous HCl (10%) wasadded to the concentrate, and the solution was extracted withdichloromethane. The organic phase was dried (MgSO₄) and then boiledover a steambath to low volume and cooled to room temperature. Theoff-white fibers were collected by vacuum filtration, rinsed withhexanes, and vacuum-oven dried. (76° C.; ca. 10 mm of Hg) to afford 1.10g (47%) of the desired material; mp 224-229.5° C.;

[0045]¹H NMR (400 MHz; DMSO): Λ 9.72 (s, 1H), 7.97 (dd, 1H, J=7.0, 8.7Hz), 7.70 (d, 1H, J=1.5 Hz), 7.57 (dd, 1H, J=8.4, 1.9 Hz), 7.17 (d, 1H,J=8.2 Hz), 6.61-6.53 (m, 2H), 2.18 (s, 3H);

[0046]¹³C NMR (100 MHz; DMSO): Λ 169.87,167.60,165.12,150.17,150.05,139.83, 138.49, 136.07, 135.31, 135.20, 135.07, 125.60,109.32, 105.09, 104.87, 99.72, 99.46, 89.43, 17.52;

[0047]¹⁹F NMR (376 MHz; DMSO): δ −104.00 to −104.07 (m);

[0048] IR (KBr) 1670 (C=O stretch) cm⁻¹;

[0049] MS (CI) M+1=372.

[0050] Analysis calculated for C₁₄H₁₁FINO₂: C, 45.31; H, 2.99; N, 3.77.Found: C, 45.21; H, 2.77; N, 3.64.

EXAMPLES 2-30

[0051] By following the general procedure of Example 1, the followingbenzoic acids and salts were prepared: Example No. Compound MP ° C. 23,4,5-Trifluoro-2-(4-iodo-2-methyl- 206-210 phenylamino)-benzoic acid 33,4-Difluoro-2-(4-iodo-2-methyl- 240.5-244.5 phenylamino)-benzoic acid 45-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 259.5—262  phenylamino)-benzoic acid 5 5-Chloro-2-(2-chloro-4-iodo-phenylamino)-255-260 -benzoic acid 6 5-Chloro-2-(4-iodo-2-methyl-phenylamino)-234-238 benzoic acid 7 Sodium 5-Chloro-2-(4-iodo-2-methyl- 310-320 DECphenylamino)-benzoate 8 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-239.5-240   benzoic acid 9 2-(2-Chloro-4-iodo-phenylamino)-5-nitro-289-293 benzoic acid 10 4-Fluoro-2-(3-fluoro-4-iodo-2-methyl- 233-235phenylamino)-benzoic acid 11 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-264-267 benzoic acid 12 2-(2-Fluoro-4-iodo-phenylamino)-5-nitro- 256-258benzoic acid 13 2-(4-Bromo-2-methyl-phenylamino)-4- 218.5-220  fluoro-benzoic acid 14 2-(2-Bromo-4-iodo-phenylamino)-5-nitro- 285-288DEC benzoic acid 15 2-(4-Bromo-2-methyl-phenylamino)-3,4- 230-234difluoro-benzoic acid 16 3-Fluoro-2-(4-iodo-2-methyl-phenylamino)-218-221 benzoic acid 17 3,4-Difluoro-2-(4-iodo-2-methoxy- 230-233phenylamino)-benzoic acid 18 4-Chloro-2-(4-iodo-2-methyl-phenylamino)-245-255 DEC benzoic acid 19 2-(4-Iodo-2-methyl-phenylamino)-benzoic218-223 acid 20 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 243-46 benzoic acid 21 5-Iodo-2-(4-iodo-2-methyl-phenylamino)- 241-245 benzoicacid 22 2,3,5-Trifluoro-4-(4-iodo-2-methyl- 218-222 phenylamino)-benzoicacid 23 4-Fluoro-2-(3-chloro-4-iodo-2-methyl-   248-252.5 phenylamino)benzoic acid 24 2-(4-Iodo-phenylamino)-5-methoxy-benzoic 208-211 acid 253-Chloro-2-(2-chloro-4-iodo-phenylamino)- 232-233 benzoic acid 262-Fluoro-6-(4-iodo-2-methyl-phenylamino)- 179-182 benzoic acid 274-Fluoro2-(2,3-dimethyl-4-iodo-2-methyl- 258-261 phenylamino) benzoicacid 28 5-Methyl-2-(4-iodo-2-methyl-phenylamino)- 209.5-211   benzoicacid 29 2-Chloro-6-(4-iodo-2-methyl-phenylamino)- 171-175 benzoic acid30 2-(4-Iodo-2-methyl-phenylamino)-4-nitro- 251-263 benzoic acid

EXAMPLE 31

[0052] 5-Chloro-N-(2-hydroxyethl)-2-(4-iodo-2-methyl-phenylamino)-benzamide

[0053] To a stirring solution comprised of 0.1020 g (0.2632 mmol) of5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid, 0.1 mL (1.7 mmol)of ethanolamine, and 0.05 mL (0.29 mmol) of diisopropylethylamine in 5mL of a 1:1 (v/v) tetrahydrofuran-dichloromethane solution was added0.15 g (0.29 mmol) of solid PyBOP powder directly. The reaction mixturewas stirred at room temperature overnight. The solvent was removed invacuo. The crude residue was partitioned between ether (50 mL) and 10%aqueous hydrochloric acid (50 mL). The organic phase was washed with 10%aqueous sodium hydroxide (50 mL), dried (MgSO₄) and concentrated invacuo to afford a yellow-brown oil which was crystallized fromhexanes-ether to afford 0.0831 g (73%) of a green-yellow powder; mp120-121° C.;

[0054]¹H NMR (400 MHz; CDCl₃): δ 9.11 (s, 1H), 7.56 (d, 1H, J=1.4 Hz),7.46-7.41 (m, 2H), 7.20 (dd, 1H, J=8.9, 2.4 Hz), 7.00 (t, 2H, J=9.6 Hz),6.55 (broad t, 1H), 3.86 (t, 2H, J 5.0 Hz), 3.61 (dd, 2H, J=10.1, 5.5Hz), 2.23 (s, 3H), 1.56 (broad s, 1H);

[0055] IR (KBr) 3297 (0-H stretch), 1627 (C=O stretch) cm⁻¹;

[0056] MS (CI) M+1=431.

[0057] Analysis calculated for C₁₆H₁₆C1IN₂O₂: C, 44.62; H, 3.74; N,6.50. Found: C, 44.63; H, 3.67; N, 6.30.

EXAMPLES 32-48

[0058] By following the general procedure of Example 31, the followingbenzamides were prepared by reacting the corresponding benzoic acid withthe corresponding amine. Example No. Compound MP ° C. 324-Methoxy-N-(4-methoxy-phenyl)-3-nitro- 153.5-156   benzamide 334-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 158 benzaniide 344-Fluoro-2-(4-iodo-2-methyl-phenylamino- 102.5-104.5 N-methyl-benzamide35 N-Ethyl-4-fluoro-2-(4-iodo-2-methyl- 90-91 phenylamino)-benzamide 364-Fluoro-2-(4-iodo-2-methyl-phenylamino)- oil N,N-dimethyl-benzamide 374-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 285-288 DECN-(1H-tetrazol-5-yl)-benzamide 385-Bromo-2-(4-iodo-2-methyl-phenylamino)- 180-182 benzamide 395-Chloro-2-(4-iodo-2-methyl-phenylamino)- 137-138 N,N-dimethyl-benzamide40 [5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 170-173benzoylamno]-acetic acid 41 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-69-71 N-propyl-benzamide 42 5-Bromo-N-(2-hydroxy-ethyl)-2-   132-133.4(4-iodo-2-methyl-phenylamino)-benzamide 43N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl- oil phenylamino)-benzamide 444-Fluoro-N-{3-[4-(2-hydroxy-ethyl)- 122-124piperazin-1-yl]-propyl}-2-(4-iodo-2- methyl-phenylamino)-benzamide 45N,N-Diethyl-2-(4-iodo-2-methyl- 91-93 phenylamino)-5-nitro-benzamide 46N-Butyl-4-fluoro-2-(4-iodo-2-methyl- 97-99 phenylamino)-benzamide 475-Chloro-N,N-diethyl-2-(4-iodo-2-methyl- 118-120 phenylamino)-benzamide48 5-Bromo-2-(4-iodo-2-methyl-phenylamino- 142.5-144  N,N-dimethyl-benzamide

EXAMPLE 49

[0059] 4-Fluoro-2-(4-iodo-2-methyl-2henylamino)-benzyl alcohol

[0060] 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid (0.50 g,1.35 mmol) was dissolved in 6 mL (6 mmol) of cold 1.0 Mborane-tetrahydrofuran complex in tetrahydrofuran solution. The reactionmixture was stirred under nitrogen atmosphere at room temperatureovernight. The reaction was quenched with 80 mL of methanol.Concentration in vacuo produced a clear tan oil which was purified byMPLC. Elution with dichloromethane afforded 0.4285 g (89%) of a whitesolid; mp 99-100.5° C.;

[0061]¹H NMR (400 MHz; DMSO): δ 7.57 (d, 1H, J=1.7 Hz), 7.45 (dd, 1H,J=8.4, 1.9 Hz), 7.39 (s, 1H), 7.29 (t, 1H, J=7.5 Hz), 6.89 (d, 1H, J=8.4Hz), 6.67-6.60 (m, 1H), 5.47 (t, 1H, J=5.5 Hz), 4.49 (d, 2H, 5.1 Hz),2.14 (s, 3H);

[0062] IR (KBr) 3372 (0-H stretch) cm⁻¹;

[0063] MS (CI) M+1=358.

[0064] Analysis calculated for C₁₄H₁₃FINO: C, 47.08; H, 3.67; N, 3.92.Found: C, 47.17; H, 3.75; N, 3.72.

EXAMPLE 50-52

[0065] The following benzyl alcohols were prepared by the generalprocedure of Example 49. Example No. Compound MP ° C. 50[5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 82-85 phenyl]-methanol 51[2-(4-Iodo-2-methyl-phenylamino)-5-nitro- 126.5-128.5 phenyl]-methanol52 [5-Bromo-2-(4-iodo-2-methyl-phenylamino)- 60.5-63.5 phenyl]-methanol

[0066] Several invention compounds of Formula I were prepared utilizingcombinatorial synthetic techniques. The general procedure is as follows:

[0067] To a 0.8-mL autosampler vial in a metal block was added 40 μL ofa 0.5 M solution of the acid in DMF and 40 μL of the reagent amine (2Msolution in Hunig's base and 1 M in amine in DMF). A 0.5M solution ofPyBrop was freshly prepared and 50 μL were added to the autosamplervial. The reaction was allowed to stand for 24 hours.

[0068] The reaction mixture was transferred to a 2-dram vial and dilutedwith 2 mL of ethyl acetate. The organic layer was washed with 3 mL ofdistilled water and the water layer washed again with 2 mL of ethylacetate. The combined organic layers were allowed to evaporate todryness in an open fume hood.

[0069] The residue was taken up in 2 mL of 50% acetonitrile in water andinjected on a semi-prep reversed phase column (10 mm×25 cm, 5 μMspherical silica, pore size 115 A derivatized with C-18, the sample waseluted at 4.7 mL/min with a linear ramp to 100% acetonitrile over 8.5minutes. Elution with 100% acetonitrile continued for 8 minutes).Fractions were collected by monitoring at 214 nM. The residue wasdissolved in chloroform and transferred to a preweighed vial,evaporated, and weighed again to determine the yield.

EXAMPLES 53-206

[0070] The following compounds of Formula I were prepared bycombinatorial methodology: Example MS No. Compound M-H 535-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4- 510iodo-2-methyl-phenylamino)-benzamide 54N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo- 4622-methyl-phenylamino)-benzamide 555-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 577phenylamino)-N-(2-piperidin-1-yl-ethyl)-benzamide 563,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2- 432methyl-phenylamino)-benzamide 57N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2- 444methyl-phenylamino)-benzamide 583,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2- 446methyl-phenylamino)-benzamide 595-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 564phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)-benzamide 605-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 571phenylamino)-N-(2-pyridin-4-yl-ethyl)-benzamide 614-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 414phenylamino)-benzamide 625-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro- 5512-(4-iodo-2-methyl-phenylamino)-benzamide 635-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 580phenylamino)-N-(2-morpholin-4-yl-ethyl)- benzamide 643,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 501(2-morpholin-4-yl-ethyl)-benzamide 653,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 485(2-pyrrolidin-1-yl-ethyl)-benzamide 663,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 493(2-pyridin-4-yl-ethyl)-benzamide 67N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo- 4732-methyl-phenylamino)-benzamide 68 N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-460 phenylamino)-benzamide 692-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 384(2-hydroxy-ethyl)-benzamide 704-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2- 483morpholin-4-yl-ethyl)-benzamide 714-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3- 495piperidin-1-yl-propyl)-benzamide 723,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 513(3-piperidin-1-yl-propyl)-benzamide 734-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2- 480thiophen-2-yl-ethyl)-benzamide 744-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2- 467pyrrolidin-1-yl-ethyl)-benzamide 752-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 453(2-morpholin-4-yl-ethyl)-benzamide 765-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 557phenylamino)-N-pyridin-4-ylmethyl-benzamide 773,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N- 479pyridin-4-ylmethyl-benzamide 78 2-(4-Bromo-2-methyl-phenylamino)-N-(3-425 dimethylamino-propyl)-3,4-difluoro-benzamide 794-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 461pyridin-4-ylmethyl-benzamide 804-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2- 475pyridin-4-yl-ethyl)-benzamide 812-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 445(2-pyridin-4-yl-ethyl)-benzamide 822-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 400(3-hydroxy-propyl)-benzamide 832-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 437(2-pyrrolidin-1-yl-ethyl)-benzamide 844-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 474 phenethyl-benzamide 852-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 450(2-thiophen-2-yl-ethyl)-benzamide 862-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 431pyridin-4-ylmethyl-benzamide 872-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 444 phenethyl-benzamide88 2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N- 451(2-piperidin-1-yl-ethyl)-benzamide 895-Chloro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-  557*yl]-propyl}-2-(4-iodo-2-methyl-phenylamino)- benzamide 905-Fluoro-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-  541*yl]-propyl}-2-(4-iodo-2-methyl-phenylamino)- benzamide 912-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-pyridin- 487 4-ylmethyl-benzamide 92 5-Bromo-N-{3-[4-(2-hydroxy-ethyl)-piperazin-1-  601*yl]-propyl}-2-(4-iodo-2-methyl-phenylamino)- benzamide 935-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-  486*methyl-phenylamino)-benzamide 945-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-  497*(2-piperidin-1-yl-ethyl)-benzamide 95(3-Hydroxy-pyrrolidin-1-yl)-[2-(4-iodo-2- 466methyl-phenylamino)-5-nitro-phenyl]- 965-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-  484*(2-pyrrolidin-1-yl-ethyl)-benzamide 975-Bromo-N-(2-diethylaniino-ethyl)-2-(4-iodo-2-  530*methyl-phenylamino)-benzamide 98N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-  518*chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide 99N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-  562*bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide 100[5-Bromo-2-(4-iodo-2-methyl-phenylamino)- 499phenyl]-(3-hydroxy-pyrrolidin-1 -yl)- 1012-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic 501 acid phenethyl ester102 N-{3-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-  568 *propyl}-2-(4-iodo-2-methyl-phenylamino)- benzamide 103[5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 455phenyl]-(3-hydroxy-pyrrolidin-1-yl)- 1045-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 460pyridin-4-ylmethyl-benzamide 1055-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-  528*pyrrolidin-1-yl-ethyl)-benzamide 1065-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-  542*piperidin-1-yl-ethyl)-benzamide 1075-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-  468*pyrrolidin-1-yl-ethyl)-benzamide 1085-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-  472*methyl-phenylamino)-benzamide 109N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-  502*fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide 1105-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-  445*phenylamino)-benzamide 1115-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-  516*(4-iodo-2-methyl-phenylamino)-benzamide 1125-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-  482*(2-piperidin-1-yl-ethyl)-benzamide 1135-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-  489*phenylamino)-benzamide 114 5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3- 556* piperidin-1-yl-propyl)-benzamide 115N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-  529*(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide 1165-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-  500*morpholin-4-yl-ethyl)-benzamide 117 5-Chloro-N-(3-diethylamino-propyl)-2-(4-iodo-2-  500* methyl-phenylamino)-benzamide118 5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-  514*2-methyl-phenylamino)-benzamide 1195-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-  512*piperidin-1-yl-propyl)-benzamide 1202-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-  509*piperidin-1-yl-ethyl)-benzamide 1215-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-  544*piperazin-1-yl-ethyl)-benzamide 122N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-  470*2-methyl-phenylamino)-benzamide 1235-Bromo-N-(3-dimethylaniino-propyl)-2-(4-iodo-  516*2-methyl-phenylamino)-benzamide 124N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-  456*phenylamino)-5-nitro-benzamide 1255-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-  429*phenylamino)-benzamide 126N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-  484*methyl-phenylamino)-benzamide 127N-(3-Diethylaniino-propyl)-2-(4-iodo-2-methyl-  511*phenylamino)-5-nitro-benzamide 1285-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-  544*morpholin-4-yl-ethyl)-benzamide 1292-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-  523*piperidin-1-yl-propyl)-benzamide 130[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 439phenyl]-(3-hydroxy-pyrrolidin-1-yl) 1315-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-  558*2-methyl-phenylamino)-benzamide 1325-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-  484*(2-morpholin-4-yl-ethyl)-benzamide 1335-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-  496*piperidin-1-yl-propyl)-benzamide 134[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 482phenyl]-[4-(2-hydroxy-ethyl)-piperazin-1- 135N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-  500*(4-iodo-2-methyl-phenylamino)-benzamide 136[5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 443 benzoylamino]-acetic acid137 2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-  495*pyrrolidin-1-yl-ethyl)-benzamide 138N-(3-Dimethylamino-propyl)-2-(4-iodo-2-methyl-  483*phenylamino)-5-nitro-benzamide 139N-(2-Diisopropylamino-ethyl)-5-fluoro-2-(4-  498*iodo-2-methyl-phenylamino)-benzamide 1405-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 490 thiobenzoic acidS-phenethyl ester 141 5-Chloro-2-(4-iodo-2-methyl-phenylamino)- 506thiobenzoic acid S-phenethyl ester 1425-Bromo-2-(4-iodo-2-methyl-phenylamino)- 536 thiobenzoic acid S-benzylester 143 2-(4-Iodo-2-methyl-phenylaniino)-5-nitro- 503 thiobenzoic acidS-benzyl ester 144 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 476thiobenzoic acid S-benzyl ester 1455-Chloro-2-(4-iodo-2-methyl-phenylamino)- 492 thiobenzoic acid S-benzylester 146 N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl- 409phenylamino)-benzamide 147 5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2- 429methyl-phenylamino)-benzamide 1485-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2- 413methyl-phenylamino)-benzamide 149N-Benzy1oxy-5-fluoro-2-(4-iodo-2-methyl- 475 phenylamino)-benzamide 150N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-  593* phenylamino)-benzamide 1512-(4-Iodo-2-methyl-phenylamino)-5-nitro-N- 567(4-sulfamoyl-benzyl)-benzamide 1525-Bromo-N-(2-hydroxy-ethy1l-2-(4-iodo-2- 473methyl-phenylamino)-benzamide 153N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl- 521phenylamino)-benzamide 154 N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl- 440phenylamino)-5-nitro-benzamide 1552-(4-Iodo-2-methyl-phenylamino)-N-methyl-5- 486 nitro-N-phenyl-benzamide156 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl- 425phenylamino)-benzamide 157 5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-459 methyl-N-phenyl-benzamide 158 N-Allyl-5-fluoro-2-(4-iodo-2-methyl-409 phenylamino)-benzamide 159 N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-583 phenylamino)-benzamide 1605-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 538(4-sulfamoyl-benzyl)-benzaniide 161N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)- 425 benzamide 162N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 436 5-nitro-benzamide 1635-Bromo-N-cyclopropy1-2-(4-iodo-2-methyl- 469 phenylamino)-benzamide 1645-Chloro-2-(4-iodo-2-methyl-phenylamino)-N- 475methyl-N-phenyl-benzamide 1655-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4- 646sulfamoyl-benzyl)-benzamide 1665-Bromo-2-(4-iodo-2-methyl-phenylanino)-N-(4- 598sulfamoyl-benzyl)-benzamide 167N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5- 436 nitro-benzamide 1682-(4-Iodo-2-methyl-phenylamino)-5-nitro-N- 565(4-sulfamoyl-benzyl)-benzamide 169 N-Allyl-5-bromo-2-(4-iodo-2-methyol-469 phenylamino)-benzamide 1705-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 473(3-methyl-benzyl)-benzamide 171 N-Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-517 phenylamino)-benzamide 1725-Bromo-2-(4-iodo-2-methyl-phenylamino)-N- 519 methyl-N-phenyl-benzamide173 N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)- 502 5-nitro-benzamide174 N-Cyclohexyl-5-iodo-2-(4-iodo-2-methyl- 559 phenylamino)-benzamide175 N-Allyl-5-iodo-2-(4-iodo-2-methyl- 517 phenylamino)-benzamide 1765-Iodo-2-(4-iodo-2-methy1-phenylamino)-N- 581(3-methyl-benzyl)-benzamide 1772-(4-Iodo-2-methyl-phenylamino)-N-(3-methyl- 500benzyl)-5-nitro-benzamide 178 5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-567 methyl-N-phenyl-benzamide 179N-Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl- 451 phenylamino)-benzamide 1805-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl- 467 phenylamino)-benzamide 1815-Bromo-2-(4-iodo-2-methyl-phenylamino)-N- 533(3-methyl-benzyl)-benzamide 182 5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-511 phenylamino)-benzamide 1835-Chloro-2-(4-iodo-2-methyl-phenylamino)-N- 489(3-methyl-benzyl)-benzamide 184N-Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)- 478 5-nitro-benzamide 185N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl- 538 phenylamino)-benzamide 186N-Benzy1oxy-5-fluoro-2-(4-iodo-2-methyl- 477 phenylamino)-benzamide 1875-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2- 431methyl-phenylamino)-benzamide 1885-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 475phenylamino)-benzamide 189 2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-488 nitro-N-phenyl-benzamide 1905-Chloro-2-(4-iodo-2-methyl-phenylamino)-N- 477methyl-N-phenyl-benzamide 191N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl- 523phenylamino)-benzamide 192 5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-425 phenylamino)-benzamide 193N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)- 427 benzamide 1945-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 461methyl-N-phenyl-benzamide 195 N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-442 phenylamino)-s-nitro-benzamide 1965-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl- 415phenylamino)-benzamide 197 5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl- 472phenylamino)-benzamide 198 N-Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-411 phenylamino)-benzamide 1995-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N- 540(4-sulfamoyl-benzyl)-benzamide 200N-Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)- 438 5-nitro-benzamide 201N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)- 411 benzamide 202N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl- 585 phenylamino)-benzamide 203N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)- 472 benzamide 2045-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4- 601sulfamoyl-benzyl)-benzamide 2055-Bromo-2-(4-iodo-2-methyl-phenylamino)-N- 522 methyl-N-phenyl-benzamide206 N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5- 438 nitro-benzamide

EXAMPLE 207

[0071] Preparation of[4-Chloro-2-(1H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine

[0072] Step a: Preparation of 5-Chloro-2-fluoro-benzaldehyde

[0073] To a solution of 1-chloro-4-fluorobenzne (13.06 g, 0.1 mol) inTHF (180 mL), at −78° C., LDA (2 M solution in THF, 50 mL, 0.1 mol) wasadded dropwise. After stirring at −78° C. for 1.5 hours, DMF (8 mL) wasadded to the reaction mixture and allowed to warm up to room temperatureovernight. The reaction mixture was partitioned between water and Et₂O.The Et₂O layer was dried (MgSO₄) and the solvent removed in vacuum togive 14.95 g (94%) yield of crude aldehyde:

[0074]¹H NMR (CDCl₃): δ, 10.3 (s, —C(═O)H).

[0075] Step b: Preparation of 5-Chloro-2-fluoro-benzaldehyde oxime

[0076] A solution of 5-chloro-2-fluoro-benzaldehyde (10 g, 0.0631 mol),hydroxylamine hydrochloride (6.57 g, 0.0946 mol) and pyridine (8.3 mL,0.1010 mol) in EtOH (100 mL) was heated at 75° C. (oil bath temperature)for 1 hour and the solvent removed under vacuum to give an oil. The oilwas partitioned between water and CH₂Cl₂. The CH₂Cl₂ layer was dried(MgSO₄) and the solvent removed under vacuum to give crude aldoxime as asolid. The solid was purified by medium pressure liquid chromatographyon silica. Elution with CH₂CL₂ gave 4.87 g (28%) of the aldoxime aswhite solid: mp 95-97° C.;

[0077] Analysis calculated for C₇H₅NOFCl: C, 48.44; H, 2.90; N, 8.07.Found: C, 48.55; H, 2.69, N, 7.90.

[0078] Step c: Preparation of 5-Chloro-2-fluoro-benzonirile

[0079] A solution of the 5-chloro-2-fluoro-benzaldehyde oxime (3.15 g,0.0182 mol) in acetic anhydride (150 mL) was refluxed for 16 hours. Thereaction mixture was cooled to room temperature and poured intosaturated aqueous NaHCO₃ (200 mL) solution. The mixture was extractedwith Et₂O. The Et₂O layer was dried (K₂CO₃) and the solvent removed togive the product as an oily solid. The product was used without furtherpurification in the next step.

[0080] Step d: Preparation of 5-(5-Chloro-2-fluoro-phenyl)-1H-tetrazole

[0081] A mixture of 5-chloro-2-fluoro-benzonitrile (2.84 g, 0.01823mol), butanol (15 mL), sodium azide (1.543 g, 0.0237 mol), acetic acid(1.36 mL, 0.0237 mol) was refluxed for 24 hours. The reaction mixturewas cooled to room temperature, additional 1.543 g sodium azide added,and the reaction mixture refluxed for additional 24 hours. After coolingto room temperature, Et₂O (100 mL) and 10% aqueous NaOH (200 mL) wereadded sequentially. The mixture was vigorously stirred. The aqueouslayer was separated, cooled with ice-methanol bath (-15° C.) andacidified to pH 1 with conc. HCl. A gray solid precipitated. The solidwas dried in vacuum at 50° C. to give 1.76 g (49%) of5-(5-chloro-2-fluoro-phenyl)-1H-tetrazole: mp partial melt at 110° C.,complete melting at 124° C.);

[0082]¹H (400 Mz, CDCl₃): δ 8.19-8.08 (m, 1H), 7.77-7.71 (m, 1H),7.61-7.52 (m, 1H);

[0083]¹³C (100 Mz, CDCl₃): δ 159.00, 156.49, 140.88, 133.02, 132.93,130.73, 129.23, 129.21, 129.08, 126.05,118.96, 118.73, 114.50;

[0084] MS (CI) M+1=199 (100), M=198 (6).

[0085] Step e: Preparation of[4-Chloro-2-(1H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine

[0086] To a solution of 2-methyl-4-iodoaniline (3.52 g, 0.0151 mol) inTHF (25 mL) at −78° C., LDA (2 molar solution in THF, 11.33 mL, 0.02267mol) was added dropwise. After stirring for 0.5 hours, a solution of1-(tetrazol-5-yl)-2-fluoro-5-chlorobenzene (1.5 g, 0.00756 mol) in THF(15 mL) was added dropwise. The reaction was stirred for 16 hours as itwarmed up to room temperature. The reaction mixture was quenched withaqueous conc. NH₄Cl solution and extracted with CH₂Cl₂. The organiclayer was dried (MgSO₄) and the solvent removed giving a crude productas an oil. The oil with CH₂Cl₂→CH₂CI₂:MeOH (9.7:0.3) gave 1.5 g (48%) ofthe desired product: mp 205-208;

[0087]¹H (400 Mz, DMSO): δ 9.13 (s, 1H), 8.00-7.99 (s, 1H), 7.69 (s,1H), 7.55-7.52 (m, 1H), 7.43-7.40 (m, 1H), 7.12-7.05 (m, 1H), 2.24 (s,3H);

[0088]¹³C (100 Mz, CDCl₃): δ 141.87, 139.28, 138.88, 135.47, 133.71,131.65, 128.15, 123.69, 121.94, 116.68, 87.79, 17.22;

[0089] MS (CI) M+2=413 (44), M+1=412 (85), M=411 (100).

[0090] Analysis calculated for C₁₄H₁₁N₅ClI.0.5H₂O: C, 39.97; H, 2.87; N,16.65. Found: C, 38.87, H, 2.77; N, 16.47.

[0091] The following tetrazole substituted phenylamines were prepared byfollowing the general procedure of Example 207.

EXAMPLE 208

[0092] (4-Iodo-2-methyl-phenyl)-[2-(1H-tetrazol-5-yl)-phenyllamine, mp231° C. (dec)

EXAMPLE 209

[0093] [4-Nitro-2-(1H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine, mp205-208° C.

[0094] The invention compounds are useful in treating cancer and otherproliferative diseases by virtue of their selective inhibition of thedual specificity protein kinases MEK₁ and MEK₂. The invention compoundhas been evaluated in a number of biological assays which are normallyutilized to establish inhibition of proteins and kinases, and to measuremitogenic and metabolic responses to such inhibition.

EXAMPLES 210-224

[0095] Additional invention compounds which were prepared by the generalmethods described above are: Example No. Compound MP ° C. 2102-(2-Chloro-4-iodo-phenylamino)-3- 239-241 DECfluoro-4-(2-morpholin-4-yl- ethylamino)-5-nitro-benzoic acid 2114-Amino-2-(2-chloro-4-iodo-phenylamino)- >270 3-5-nitro-benzoic acid 2122,4-Bis-(2-chloro-4-iodo-phenylamino)-3- >265 DEC fluoro-5-nitro-benzoicacid 213 4-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 218-225 DEC5-nitro-benzoic acid 214 2-(2,6-Difluoro-4-iodo-phenylamino)-3,4-247-249 benzoic acid 215 2-(2-Chloro-4-iodo-phenylamino)-4-nitro-267-269 benzoic acid 216 2-(2,4-Diiodo-phenylamino)-4-fluoro- 260-261benzoic acid 217 2-(2-Bromo-4-iodo-phenylamino)A-fluoro- 259-262 benzoicacid 218 4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)- 215-217 benzoic acid219 2-(2-Chloro-4-iodo-phenylamino)-4-fluoro- 242-247 benzoic acid 2205-Bromo-2-(2-chloro-4-iodo-phenylamino)- 312.5-318  3,4-difluoro-benzoic acid 221 2,3,5-Trifluoro-6-(4-iodo-2-methyl-118-121 phenylamino)-4-(4-methyl-piperazin-1-yl)- benzoic acid methylester dihydrofluoride salt 222 5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-214-217 DEC phenylamino)-N-(4-methyl-piperazin-1-yl)- benazmide 2235-Bromo-3,4-difluoro-2-(4-iodo-2-methyl- 154-175 DECphenylamino)-benzoic acid N′,N′- dimethyl-hydrazide 2244-Fluoro-2-(4-iodo-2-methyl-phenylamino)- 153.5-156   benzoic acidhydrazide

[0096] Enzyme Assays

[0097] Cascade Assay for Inhibitors of the MAP Kinase Pathway

[0098] Incorporation of ³²P into myelin basic protein (MBP) was assayedin the presence of a glutathione S-transferase fusion protein containingp44MAP kinase (GST-MAPK) and a glutathione S-transferase fusion proteincontaining p45MEK (GST-MEK). The assay solution contained 20 mM HEPES,pH 7.4, 10 mM MgCl₂, 1 mM MnCl₂, 1 mM EGTA, 50 μM [γ-³²P]ATP, 10 μgGST-MEK0.5 μg GST-MAPK and 40 μg MBP in a final volume of 100 μL.Reactions were stopped after 20 minutes by addition of trichloroaceticacid and filtered through a GF/C filter mat. ³²P retained on the filtermat was determined using a 1205 Betaplate. Compounds were assessed at 10μM for ability to inhibit incorporation of ³²P.

[0099] To ascertain whether compounds were inhibiting GST-MEK or GSTMAPK, two additional protocols were employed. In the first protocol,compounds were added to tubes containing GST-MEK, followed by additionof GST-MAPK, MBP and [γ-³²P]ATP. In the second protocol, compounds wereadded to tubes containing both GST-MEK and GST-MAPK, followed by MBP and[γ-³²P]ATP. Compounds that showed activity in both protocols were scoredas MAPK inhibitors, while compounds showing activity in only the firstprotocol were scored as MEK inhibitors.

[0100] In Vitro MAP Kinase Assay

[0101] Inhibitory activity was also confirmed in direct assays. For MAPkinase, 1 μg GST-MAPK was incubated with 40 μg MBP for 15 minutes at 30°C. in a final volume of 50 μL containing 50 mM Tris (pH 7.5), 10 μMMgCl₂, 2 μM EGTA, and 10 μM [γ-³²P]ATP. The reaction was stopped byaddition of Laemmli SDS sample buffer and phosphorylated MBP resolved byelectrophoresis on a 10% polyacrylamide gel. Radioactivity incorporatedinto MBP was determined by autoradiography, and subsequently by excisionof the bands followed by scintillation counting.

[0102] In Vitro MEK Assay

[0103] For evaluation of direct MEK activity, 10 μg GST-MEK₁ wasincubated with 5 μg of a glutathione S-transferase fusion proteincontaining p44MAP kinase with a lysine to alanine mutation at position71 (GST-MAPK-KA). This mutation eliminates kinase activity of MAPK, soonly kinase activity attributed to the added MEK remains. Incubationswere 15 minutes at 30° C. in a final volume of 50 μL containing 50 mMTris (pH 7.5), 10 μM MgCl₂, 2 μM EGTA, and 10 μM [γ-³²P]ATP. Thereaction was stopped by addition of Laemmli SDS sample buffer andphosphorylated GST-MAPK-KA was resolved by electrophoresis on a 10%polyacrylamide gel. Radioactivity incorporated into GST-MAPK-KA wasdetermined by autoradiography, and subsequently by excision of the bandsfollowed by scintillation counting. Additionally, an artificiallyactivated MEK was utilized that contained serine to glutamate mutationsat positions 218 and 222 (GST-MEK-2E). When these sites arephosphorylated, MEK activity is increased. Phosphorylation of thesesites can be mimicked by mutation of the serine residues to glutamate.For this assay, 5 μg GST-MEK-2E was incubated with 5 μg GST-MAPK-KA for15 minutes at 30° C. in the same reaction buffer as described above.Reactions were terminated and analyzed as above.

[0104] Whole Cell MAP Kinase Assay

[0105] To determine if compounds were able to block activation of MAPkinase in whole cells, the following protocol was used: Cells wereplated in multi-well plates and grown to confluence. Cells were thenserum-deprived overnight. Cells were exposed to the desiredconcentrations of compound or vehicle (DMSO) for 30 minutes, followed byaddition of a growth factor, for example, PDGF (100 ng/mL). After a5-minute treatment with the growth factor, cells were washed with PBS,then lysed in a buffer consisting of 70 mM NaCl, 10 mM HEPES (pH 7.4),50 mM glycerol phosphate, and 1% Triton X-100. Lysates were clarified bycentrifugation at 13,000× g for 10 minutes. Five micrograms of theresulting supernatants were incubated with 10 μg microtubule associatedprotein-2 (Map2) for 15 minutes at 30° C. in a final volume of 25 μLcontaining 50 mM Tris (pH 7.4), 10 mM MgCl₂, 2 mM EGTA and 30 uM[γ-³²P]ATP. Reactions were terminated by addition of Laemmli samplebuffer. Phosphorylated Map2 was resolved on 7.5% acrylamide gels andincorporated radioactivity determined by autoradiography and subsequentexcision of the bands followed by scintillation counting.

[0106] Immunoprecipitation and Antiphosphotyrosine Immunoblots

[0107] To determine the state of tyrosine phosphorylation of cellularMAP kinase, cells were lysed, endogenous MAP kinase wasimmunoprecipitated with a specific antibody, and the resultingimmunoprecipitate analyzed for the presence of phosphotyrosine asfollows: confluent cells were serum-deprived overnight and treated withcompounds and growth factors as described above. Cells were then scrapedand pelleted at 13,000× g for 2 minutes. The resulting cell pellet wasresuspended and dissolved in 100 μL of 1% SDS containing 1 mM NaVO₄.Following alternate boiling and vortexing to denature cellular protein,900 μL RIPA buffer (50 mM Tris (pH 7.4), 150 mM NaCl, 1% Triton X-100,0.1% deoxycholate, and 10 mM EDTA) was added. To this mixture was added60 μL agarose beads coupled with rabbit immunoglobulin G and 60 μLPansorbin cells in order to clear the lysate of nonspecific bindingproteins. This mixture was incubated at 4° C. for 15 minutes thencentrifuged at 13,000× g for 10 minutes. The resulting supernatant wastransferred to fresh tubes and incubated with 10 μL of a polyclonalantisera raised against a fragment of MAP kinase for a minimum of 1 hourat 4° C. Seventy microliters of a slurry of agarose beads coupled withprotein G and protein A was added and the incubation continued for anadditional 30 minutes at 4° C. The beads were pelleted by centrifugationat 13,000× g for 5 minutes and washed three times with 1 mL RIPA buffer.Laemmli sample buffer was added to the final bead pellet. This mixturewas boiled for 5 minutes then resolved on a 10% acrylamide gel. Proteinson the gel were transferred to a nitrocellulose membrane and nonspecificbinding sites on the membrane blocked by incubation with 1% ovalbuminand 1% bovine serum albumin in TBST (150 mM NaCl, 10 mM Tris (pH 7.4),and 0.05% Tween 20). The membrane was then incubated with a commerciallyavailable antibody directed against phosphotyrosine. Antibody bound onthe membrane was detected by incubation with ¹²⁵I-protein A, followed byautoradiography.

[0108] Cell Growth Assays

[0109]³H-Thymidine incorporation

[0110] Cells were plated in multi-well plates and grown to nearconfluence. The media was then removed and replaced with growth mediacontaining 1% bovine serum albumin. After 24-hour serum starvation,compounds and specific growth factors were added and incubationscontinued for an additional 24 hours. During the final 2 hours,³H-thymidine was added to the medium. To terminate the incubations, themedium was removed and cell layers washed twice with ice-coldphosphate-buffered saline. After the final wash, ice-cold 5%trichloroacetic acid was added and the cells incubated for 15 minutes atroom temperature. The trichloroacetic acid solution was then removed andthe cell layer washed three times with distilled water. After the finalwash, the cell layer was solubilized by addition of 2% sodiumdodecylsulfate. Radioactivity in this solution was determined byscintillation counting.

[0111] In 3T3-L1 adipocyte cells, in which the inhibition blocks MAPKactivation by insulin with an IC₅₀ of 3 μM, the compound had no effecton the insulin stimulated uptake of radiolabeled 2-deoxyglucose, or onthe insulin-stimulated synthesis of either lipid or glycogen at 10 μMconcentration. This demonstrates that the inhibitor shows selectivitybetween the mitogenic and metabolic effects of insulin, and demonstratesthat the inhibitor will show less toxicity than an inhibitor which doesnot show this surprising selectivity.

[0112] Monolayer Growth

[0113] Cells were plated into multi-well plates at 10 to 20,000cells/mL. Forty-eight hours after seeding, compounds were added to thecell growth medium and incubation was continued for 2 additional days.Cells were then removed from the wells by incubation with trypsin andenumerated with a Coulter counter.

[0114] Growth in Soft-agar

[0115] Cells were seeded into 35-mm dishes at 5 to 10,000 cells/dishusing growth medium containing 0.3% agar. After chilling to solidify theagar, cells were transferred to a 37° C. incubator. After 7 to 10 daysgrowth, visible colonies were manually enumerated with the aid of adissecting microscope. Order of addition experiments established thatthe invention compounds are inhibiting MEK and not MAP kinase.Experiments looking at the phosphorylation of a kinase defective mutantof MAP kinase as substrate (so that there can be no autophosphorylationof the MAP kinase to complicate interpretation) confirms that theinhibitor inhibits MEK with an IC₅₀ essentially identical to thatproduced in the cascade assay.

[0116] Kinetic analysis demonstrates that the invention compounds arenot competitive with ATP. Thus, they do not bind at the ATP binding siteof the enzyme, which is probably the explanation as to why thesecompounds do not show the nonspecific kinase inhibitory activity typicalof most kinase inhibitors, which do bind at the ATP binding site andwhich are ATP competitive. The in vitro and in vivo biological activityof several representative compounds of Formula I in the foregoing assaysis presented in Table 1. TABLE 1 In Vitro In Vivo (CellCulture) Compoundof % IC₅₀ % IC₅₀ Example No. Inhibition μM Inhibition μM 1 0.019 2 0.0143 3 0.0111 10 4 0.005 5 0.066 6 0.071 7 0.072 8 0.086 9 0.097 10 0.10111 0.128 12 0.135 13 0.178 14 0.179 15 0.194 16 0.323 17 0.434 18 0.44619 0.524 50% at 30 μM 20 0.557 21 0.569 22 1.581 30% at 30 μM 23 1.58824 1.944 25 2.363 26 2.609 50% at 30 μM 27 2.269 28 3.670 29 5.331 30105 10 31 0.226 32 0.028 33 0.052 34 0.098 35 0.121 36 0.129 37 0.237 380.412 39 0.497 40 0.651 30% at 30 μM 41 0.872 42 0.920 43 >1.000 441.481 45 1.755 46 1.814 47 1.911 48 1.945 49 0.418 3 50 0.179 51 0.88752 2.346 53 0.047 0.54 54 0.158 55 0.114 57 0.399 89 0.186 89 0.614 900.604 91 2.071 92 0.253 93 0.521 95 1.001 96 0.374 100 1.994 184 0.278186 0.555 187 0.561 188 0.771 189 0.859 190 0.921 191 1.355 192 1.797193 2.902 194 4.952 195 12.831 208 1.215 209 1.372 211 >0.1 212 0.034213 0.062 214 0.303 215 0.031 216 1.000 217 >1.00 218 0.051 219 0.108220 0.029 221 0.002 222 0.085 223 0.043 224 0.028

[0117] The invention compounds will be utilized to treat subjectssuffering from cancer and other proliferative diseases,immunodeficiency, and certain degenerative diseases, and in need oftreatment. The compounds are ideally suited to treating psoriasis,restenosis, autoimmune disease, and atherosclerosis. The compounds willgenerally be utilized as a pharmaceutical formulation, in which thecompound of Formula I is present in a concentration of about 5% to about95% by weight. The compounds can be formulated for convenient oral,parenteral, topical, rectal, or like routes of administration. Thecompound will be formulated with common diluents, excipients, andcarriers routinely utilized in medicine, for instance, with polyols suchas glycerin, ethylene glycol, sorbitol 70; mono- and difatty acid estersof ethylene glycol. Starches and sugars such as corn starch, sucrose,lactose, and the like, can be utilized for solid preparations. Suchsolid formulations can be in the form of tablets, troches, pills,capsules, and the like. Flavoring agents such as peppermint, oil ofwintergreen, and the like can be incorporated.

[0118] Typical doses of active compound are those that are effective totreat the cancer or other proliferative disorder afflicting the mammal.Doses will generally be from about 0.1 mg per kilogram body weight toabout 500 mg per kilogram body weight. Such doses will be administeredfrom one to about four times a day, or as needed to effectively treatthe cancer, psoriasis, restenosis, or other proliferative disorder.

[0119] A preferred method for delivering the invention compound isorally via a tablet, capsule, solution, or syrup. Another method isparenterally, especially via intravenous infusion of a solution of thebenzopyran in isotonic saline or 5% aqueous glucose.

[0120] Following are typical formulations provided by the invention.

EXAMPLE 225

[0121] Preparation of 50-mg Tablets Per Tablet Per 10,000 Tablets 0.050g 4-fluoro-2-(4-iodo-2-methyl- 500 g phenylamino)-benzoic acid 0.080 glactose 800 g 0.010 g corn starch (for mix) 100 g 0.008 g corn starch(for paste)  80 g 0.002 g magnesium stearate (1%)  0 g 0.150 g 1500 g 

[0122] The benzoic acid, lactose, and corn starch (for mix) are blendedto uniformity. The corn starch (for paste) is suspended in 600 mL ofwater and heated with stirring to form a paste. The paste is used togranulate the mixed powders. The granules are passed through a #8 screenand dried at 120° F. The dry granules are passed through a #16 screen.The mixture is lubricated with 1% magnesium stearate and compressed intotablets. The tablets are administered to a mammal for inhibiting MEKenzymes and treating restenosis, atherosclerosis, and psoriasis.

EXAMPLE 226

[0123] Preparation of Oral Suspension Ingredient Amount5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N- 500 mg (methyl)-benzamideSorbitol solution (70% NF)  40 mL Sodium benzoate 150 mg Saccharin  10mg Red dye  10 mg Cherry flavor  50 mg Distilled water qs ad 100 mL

[0124] The sorbitol solution is added to 40 mL of distilled water andthe benzamide derivative is suspended therein. The saccharin, sodiumbenzoate, flavor, and dye are added and dissolved. The volume isadjusted to 100 mL with distilled water. Each milliliter of syrupcontains 5 mg of the invention compound. The syrup is administered to amammal for treating proliferative disease, especially breast cancer andskin cancer.

EXAMPLE 227

[0125] Preparation of Parenteral Solution

[0126] In a solution of 700 mL of propylene glycol and 200 mL of waterfor injection is added 20.0 g of4-fluoro-2-(4-bromo-2-methyl-phenylamino)-benzyl alcohol. The volume ofthe solution is adjusted to 1000 mL by addition of water for injection.The formulation is heat sterilized, filled into 50-mL ampoules eachcontaining 2.0 mL (40 mg of4-fluoro-2-(4-bromo-2-methyl-phenylamino)-benzyl), and sealed undernitrogen.

[0127] The invention compound thus formulated will be administered to amammal in need of treatment for a proliferative disorder such as cancer,psoriasis, restenosis, atherosclerosis, autoimmune disease, and otherimmunodeficient diseases and degenerative disorders, at a rate and doseeffective to treat the condition. An “antiproliferative amount” of aninvention compound is that quantity of compound that inhibits or reducesthe rate of proliferation of target cells. Typical cancers to be treatedaccording to this invention include breast cancer, colon cancer,prostate cancer, skin cancer, and the like. The invention compound isespecially well-suited for use in combination with radiation fortreating cancer. The compound is well-suited to the treatment ofpsoriasis, restenosis, and atherosclerosis, and to inhibiting theactivity of MEK enzymes, especially MEK₁ and MEK₂. All that is requiredto inhibit these enzymes is to administer to a mammal an MEK inhibitingamount of a compound of the invention. An “MEK inhibiting amount” of aninvention compound is an amount that when administered to a mammalcauses a measurable inhibition of the MEK enzyme. Typical MEK inhibitingamounts will be from about 0.1 μg to about 500 mg of active compound perkilogram body weight. For treating the proliferative diseases mentionedabove, typical doses will be from about 0.1 to about 50 mg/kg, normallygiven from one to about four times per day.

We claim:
 1. The compounds of Formula I

wherein: R₁ is hydrogen, hydroxy, C₁-C₈ alkyl, C₁-C₈ alkoxy, halo,trifluoromethyl, or CN; R₂ is hydrogen; R₃, R₄, and R₅ independently arehydrogen, hydroxy, halo, trifluoromethyl, C₁-C₈ alkyl, C₁-C₈ alkoxy,nitro, CN, or —(O or NH)_(m)—(CH₂)_(n)-R₉, where R₉ is hydrogen,hydroxy, COOH, or NR₁₀R₁₁; n is 0-4; m is 0 or 1; R₁₀ and R₁₁independently are hydrogen or C₁-C₈ alkyl, or taken together with thenitrogen to which they are attached can complete a 3-10 member cyclicring optionally containing 1, 2, or 3 additional heteroatoms selectedfrom O, S, NH, or N—C₁-C₈ alkyl; Z is COOR₇, tetrazolyl, CONR₆R₇,CONHNR₁₀R₁₁, or CH₂OR₇; R₆ and R₇ independently are hydrogen, C₁-C₈alkyl, C₂-C₈ alkenyl, C₂-C₈ alkynyl,

aryl, heteroaryl, C₃-C₁₀ cycloalkyl, or C₃-C₁₀ (cycloalkyl optionallycontaining one, two, or three heteroatoms selected from O, S, NH, or Nalkyl); or R₆ and R₇ together with the nitrogen to which they areattached complete a 3-10 member cyclic ring optionally containing 1, 2,or 3 additional heteroatoms selected from O, S, NH, or N alkyl; andwherein any of the foregoing alkyl, alkenyl, and alkynyl groups can beunsubstituted or substituted by halo, hydroxy, alkoxy, amino,alkylamino, dialkylamino, cycloalkyl, aryl, aryloxy, heteroaryl, orheteroaryloxy, and the pharmaceutically acceptable salts thereof.
 2. Acompound according to claim 1 wherein R₁ is CH₃ or halo.
 3. A compoundaccording to claim 2 wherein Z is COOR₇, tetrazolyl, or a salt thereof.4. A compound according to claim 3 which is[4-Chloro-2-(1H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine;(4-Iodo-2-methyl-phenyl)-[2-(1H-tetrazol-5-yl)-phenyl]amine; and[4-Nitro-2-(1H-tetrazol-5-yl)-(4-iodo-2-methyl-phenyl)-amine.
 5. Acompound according to claim 3 having the formula


6. A compound of claim 5 wherein R₃ is hydrogen, fluoro, or chloro; R₄is hydrogen, fluoro, chloro, or nitro; and R₅ is hydrogen, chloro,fluoro, bromo, nitro, or methoxy.
 7. A compound of claim 6 which is4-Fluoro-2-(4-iodo-2-methylphenylamino)benzoic acid;3,4,5-Trifluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid; Sodium5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoate;5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;2-(4-Iodo-2-methyl-phenylamino)-5-nitro-benzoic acid;4-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;2-(4-Iodo-2-methyl-phenylamino)-benzoic acid;5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;5-Iodo-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;2,3,5-Tifluoro-4-(4-iodo-2-methyl-phenylamino)-benzoic acid;2-(4-Iodo-phenylamino)-5-methoxy-benzoic acid;5-Methyl-2-(4-iodo-2-methyl-phenylamino)-benzoic acid;2-(4-Iodo-2-methyl-phenylamino)-4-nitro-benzoic acid;4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzoic acid;2,3,5-Trifluoro-6-(4-iodo-2-methyl-phenylamino)-4-(4-methyl-piperazin-1-yl)-benzoicacid methyl ester dihydrofluoride salt; 1-yl)-benazmide;5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acidN′,N′-dimethyl-hydrazide; and4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid hydrazide.
 8. Acompound of claim 3 having the formula


9. A compound of claim 8 wherein R₃ is hydrogen, chloro, or fluoro; R₄is hydrogen, chloro, fluoro, or nitro; R₅ is hydrogen, chloro, fluoro,bromo, nitro, or methoxy.
 10. A compound of claim 1 which is2-(4-Bromo-2-methyl-phenylamino)-4-fluoro-benzoic acid;2-(2-Bromo-4-iodo-phenylamino)-5-nitro-benzoic acid;2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-benzoic acid;2-(2-Chloro-4-iodo-phenylamino)-3-fluoro-4-(2-morpholin4-yl-ethylamino)-5-nitro-benzoicacid; 4-Amino-2-(2-chloro-4-iodo-phenylamino)-3-fluoro-5-nitro-benzoicacid; 2,4-Bis-(2-chloro-4-iodo-phenylamino)- 3-fluoro-5-nitro-benzoicacid; 2-(2-Chloro4-iodo-phenylamino)-4-nitro-benzoic acid;2-(2,4-Diiodo-phenylamino)-4-fluoro-benzoic acid;2-(2-Bromo-4-iodo-phenylamino)-4-fluoro-benzoic acid;4-Fluoro-2-(2-fluoro-4-iodo-phenylamino)-benzoic acid;2-(2-Chloro-4-iodo-phenylamino)-4-fluoro-benzoic acid; and5-Bromo-2-(2-chloro-4-iodo-phenylamino)-3,4-difluoro-benzoic acid.
 11. Acompound of claim 2 wherein Z is CONR₆R₇.
 12. A compound of claim 11having the formula


13. A compound of claim 12 wherein R₃ is hydrogen, chloro, or fluoro; R₄is hydrogen, chloro, fluoro, or nitro; and R₅ is hydrogen, chloro,fluoro, bromo, nitro, or methoxy.
 14. A compound of claim 13 which is5-Chloro-N-(2-hydroxyethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-benzamide;N-Ethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide;4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(1H-tetrazol-5-yl)-benzamide;5-Bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide;[5-Chloro-2-(4-iodo-2-methyl-phenylamino)-benzoylamino]-acetic acid;4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-propyl-benzamide;5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;N,N-Diethyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;4-Fluoro-N—{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iodo-2-methyl-phenylamino)-benzamide;N,N-Diethyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;N-Butyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Chloro-N,N-diethyl-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N,N-dimethyl-benzamide;5-Bromo-3,4-difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-(2,3-Dihydroxy-propyl)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)-benzamide;3,4-Difluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-(2,3-Dihydroxy-propyl)-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;3,4-Difluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl-ethyl)-benzamide;4-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Bromo-N-(3-dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)-benzamide;3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)-benzamide;3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl-ethyl)-benzamide;N-(3-Dimethylamino-propyl)-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-Benzyl-4-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-hydroxy-ethyl)-benzamide;4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)-benzamide;4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)-benzamide;3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)-benzamide;4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-thiophen-2-yl-ethyl)-benzamide;4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-morpholin-4-yl-ethyl)-benzamide;5-Bromo-3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl-benzamide;3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl-benzamide;2-(4-Bromo-2-methyl-phenylamino)-N-(3-dimethylamino-propyl)-3,4-difluoro-benzamide;4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl-benzamide;4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyridin-4-yl-ethyl)-benzamide;2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyridin-4-yl-ethyl)-benzamide;2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(3-hydroxy-propyl)-benzamide;2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-phenethyl-benzamide;2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-thiophen-2-yl-ethyl)-benzamide;2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-pyridin-4-ylmethyl-benzamide;2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-phenethyl-benzamide;2-(4-Bromo-2-methyl-phenylamino)-3,4-difluoro-N-(2-piperidin-1-yl-ethyl)-benzamide;5-Chloro-N—{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Fluoro-N—{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iodo-2-methyl-phenylamino)-benzamide;2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-pyridin-4-yl methyl-benzamide;5-Bromo-N—{3-[4-(2-hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Chloro-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)-benzamide;(3-Hydroxy-pyrrolidin-1-yl)-[2-(4-iodo-2-methyl-phenylamino)-5-nitro-phenyl];5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;5-Bromo-N-(2-diethylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide;N—{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-{3-[4-(2-Hydroxy-ethyl)-piperazin-1-yl]-propyl}-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-pyridin-4-ylmethyl-benzamide;5-Bromo-2-(4-iodo-2-ethyl-phenylamino)-N-(2-pyrrolidin-1-yI-ethyl)-benzamide;5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)-benzamide;5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-pyrrolidin-1-yl-ethyl)-benzamide;5-Chloro-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;N—{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Chloro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Chloro-N-(3-diethylamino-2-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperidin-1-yl-ethyl)-benzamide;5-Bromo-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)-benzamide;N-{2-[Bis-(2-hydroxy-ethyl)-amino]-ethyl}-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)-benzamide;5-Chloro-N-(3-diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Chloro-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)-benzamide;2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(2-piperidin-1-yl-ethyl)-benzamide;5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-piperazin-1-yl-ethyl)-benzamide;N-(2-Diethylamino-ethyl)-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Bromo-N-(3-dimethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-(3-Hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;5-Fluoro-N-(3-hydroxy-propyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-(3-Diethylamino-propyl)-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-(3-Diethylamino-propyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)-benzamide;2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(3-piperidin-1-yl-propyl)-benzamide;[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-(3-hydroxy-pyrrolidin-1-yl)-;5-Bromo-N-(2-diisopropylamino-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(2-morpholin-4-yl-ethyl)-benzamide;5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-piperidin-1-yl-propyl)-benzamide;[5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-[4-(2-hydroxy-ethyl)-piperazin-1-;N-(3-Diethylamino-2-hydroxy-propyl)-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;N—Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenyl amino)-benzamide;5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide;2-(4-lodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)-benzamide;5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-(2-Hydroxy-ethyl)-2-(4-iodo-2-ethyl-phenylamino)-5-nitro-benzamide;2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide;5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide;N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)-benzamide;N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide;N—Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;5-Bromo-N-cyclopropyl-2-(4-i odo-2-methyl-phenylamino)-benzarnide;5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide;5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)-benzamide;5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)-benzamide;N-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;2-(4-Iodo-2-methyl-phenylamino)-5-nitro-N-(4-sulfamoyl-benzyl)-benzamide;N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzamide;N—Cyclopropyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide;N-Benzyloxy-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;N—Cyclohexyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-Allyl-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-iodo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzamide;2-(4-Iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-5-nitro-benzamide;5-Iodo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide;N—Cyclohexyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Chloro-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzamide;5-Bromo-N-cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-(3-methyl-benzyl)-benzamide;N—Cyclohexyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide; N-Benzyloxy-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-Benzyloxy-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Chloro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Bromo-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;2-(4-Iodo-2-methyl-phenylamino)-N-methyl-5-nitro-N-phenyl-benzamide;5-Chloro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl benzamide;N-(2-Hydroxy-ethyl)-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Chloro-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-Allyl-5-chloro-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide;N-(2-Hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;5-Fluoro-N-(2-hydroxy-ethyl)-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Bromo-N-cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-benzamide;N—Cyclopropyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Fluoro-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)-benzamide;N—Cyclopropyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide;N-Allyl-5-fluoro-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-Benzyloxy-5-iodo-2-(4-iodo-2-methyl-phenylamino)-benzamide;N-Allyl-5-bromo-2-(4-iodo-2-methyl-phenylamino)-benzamide;5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-(4-sulfamoyl-benzyl)-benzamide;5-Bromo-2-(4-iodo-2-methyl-phenylamino)-N-methyl-N-phenyl-benzamide; andN-Allyl-2-(4-iodo-2-methyl-phenylamino)-5-nitro-benzamide.
 15. Acompound of claim 2 wherein Z is CH₂OR₇.
 16. A compound of claim 15having the formula


17. A compound of claim 16 wherein: R₃ is hydrogen, chloro, or fluoro;R₄ is hydrogen, chloro, fluoro, or nitro; and R₅ is hydrogen, chloro,fluoro, bromo, nitro, or methoxy.
 18. A compound of claim 17 which is4-Fluoro-2-(4-iodo-2-methyl-phenylamino)-benzyl alcohol;[5-Chloro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol;[2-(4-Iodo-2-methyl-phenylamino)-5-nitro-phenyl]-methanol; and[5-Bromo-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanol.
 19. Apharmaceutical formulation comprising a compound of claim 1 togetherwith a pharmaceutically acceptable excipient, diluent, or carrier.
 20. Aformulation of claim 19 comprising a compound wherein Z is COOH or asalt thereof.
 21. A formulation of claim 19 comprising a compoundwherein Z is CONR₆R₇.
 22. A formulation of claim 19 comprising acompound wherein Z is CH₂OR₇.
 23. A method for inhibiting MEK enzymes ina mammal comprising administering an MEK inhibiting amount of a compoundin claim
 1. 24. A method of treating a mammal suffering from aproliferative disease and in need of treatment comprising administeringan antiproliferative amount of a compound of claim
 1. 25. A methodaccording to claim 21 wherein the proliferative disease is psoriasis,restenosis, autoimmune disease, or atherosclerosis.
 26. A methodaccording to claim 21 wherein the proliferative disease is cancer.
 27. Amethod for treating a mammal suffering from stroke and in need oftreatment comprising administering an effective amount of a compound ofclaim
 1. 28. A method for treating a mammal suffering from heart failureand in need of treatment comprising administering an effective amount ofa compound of claim
 1. 29. A method for treating a mammal suffering fromhepatomegaly and in need of treatment comprising administering aneffective amount of a compound of claim
 1. 30. A method for treating amammal suffering from cardiomegaly and in need of treatment comprisingadministering an effective amount of a compound of claim
 1. 31. A methodfor treating a mammal suffering from diabetes and in need of treatmentcomprising administering an effective amount of a compound of claim 1.32. A method for treating a mammal suffering from Alzheimer's diseaseand in need of treatment comprising administering an effective amount ofa compound of claim
 1. 33. A method for treating a mammal suffering fromcancer and in need of treatment comprising administering an effectiveamount of a compound of claim 1 in combination with conventionalradiation therapy.
 34. A method for treating a mammal suffering fromcystic fibrosis and in need of treatment comprising administering aneffective amount of a compound of claim 1.